Rapid Evolution of HIV-1 to Functional CD8
            <sup>+</sup>
            T Cell Responses in Humanized BLT Mice

Dudek, Timothy; No, Daniel C.; Seung, Edward; Vrbanac, Vladimir; Fadda, Lena; Bhoumik, Priyasma; Boutwell, Christian L.; Power, Karen A.; Gladden, Adrianne D.; Battis, Laura; Mellors, Elizabeth F; Tivey, Trevor; Gao, Xiaojiang; Altfeld, Marcus; Luster, Andrew D.; Tager, Andrew M.; Allen, Todd M.

doi:10.1126/scitranslmed.3003984

Cited by 101 publications

(93 citation statements)

References 72 publications

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“…In this regard, results with primary CD4 ϩ T cells suggest that diminished HIV-1 replication should be observable with JRCSF replication in cohorts that express active A3H alleles (20,45). However, multiple cohorts of mice have been infected with JRCSF by three different groups, and no evidence for individual cohorts that are highly resistant to infection has been noted (17,18,36). While this evidence suggests only weak anti-HIV-1 effects for A3H, the population frequencies of A3H active alleles can be low and are highly dependent on geography (51,52).…”

Section: Resultsmentioning

confidence: 96%

See 1 more Smart Citation

APOBEC3G and APOBEC3F Act in Concert To Extinguish HIV-1 Replication

Krisko

Begum

Baker

et al. 2016

J Virol

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The multifunctional HIV-1 accessory protein Vif counters the antiviral activities of APOBEC3G (A3G) and APOBEC3F (A3F), and some Vifs counter stable alleles of APOBEC3H (A3H). Studies in humanized mice have shown that HIV-1 lacking Vif expression is not viable. Here, we look at the relative contributions of the three APOBEC3s to viral extinction. Inoculation of bone marrow/liver/thymus (BLT) mice with CCR5-tropic HIV-1 JRCSF (JRCSF) expressing a vif gene inactive for A3G but not A3F degradation activity (JRCSFvifH42/43D) displayed either no or delayed replication. JRCSF expressing a vif gene mutated to inactivate A3F degradation but not A3G degradation (JRCSFvifW79S) always replicated to high viral loads with variable delays. JRCSF with vif mutated to lack both A3G and A3F degradation activities (JRCSFvifH42/43DW79S) failed to replicate, mimicking JRCSF without Vif expression (JRCSF⌬vif). JRCSF and JRCSFvifH42/43D, but not JRCSFvifW79S or JRCSFvifH42/43DW79S, degraded APOBEC3D. With one exception, JRCSFs expressing mutant Vifs that replicated acquired enforced vif mutations. These mutations partially restored A3G or A3F degradation activity and fully replaced JRCSFvifH42/43D or JRCSFvifW79S by 10 weeks. Surprisingly, induced mutations temporally lagged behind high levels of virus in blood. In the exceptional case, JRCSFvifH42/ 43D replicated after a prolonged delay with no mutations in vif but instead a V27I mutation in the RNase H coding sequence. JRCSFvifH42/43D infections exhibited massive GG/AG mutations in pol viral DNA, but in viral RNA, there were no fixed mutations in the Gag or reverse transcriptase coding sequence. A3H did not contribute to viral extinction but, in combination with A3F, could delay JRCSF replication. A3H was also found to hypermutate viral DNA. IMPORTANCEVif degradation of A3G and A3F enhances viral fitness, as virus with even a partially restored capacity for degradation outgrows JRCSFvifH42/43D and JRCSFvifW79S. Unexpectedly, fixation of mutations that replaced H42/43D or W79S in viral RNA lagged behind the appearance of high viral loads. In one exceptional JRCSFvifH42/43D infection, vif was unchanged but replication proceeded after a long delay. These results suggest that Vif binds and inhibits the non-cytosine deaminase activities of intact A3G and intact A3F, allowing JRCSFvifH42/43D and JRCSFvifW79S to replicate with reduced fitness. Subsequently, enhanced Vif function is acquired by enforced mutations. In infected cells, JRCSF⌬vif and JRCSFvifH42/43DW79S are exposed to active A3F and A3G and fail to replicate. JRCSFvifH42/43D Vif degrades A3F and, in some cases, overcomes A3G mutagenic activity to replicate. Vif may have evolved to inhibit A3F and A3G by stoichiometric binding and subsequently acquired the ability to target these proteins to proteasomes.

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Section: Resultsmentioning

confidence: 96%

“…BLT mice were prepared as previously described (32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43) . Following a 10-min incubation at room temperature, the lysed blood was centrifuged at 10,000 rpm for 1 min, and the lysis buffer was removed by aspiration.…”

Section: Cell Culture Tzm Hela Cells Obtained From the Nih Aids Resementioning

confidence: 99%

APOBEC3G and APOBEC3F Act in Concert To Extinguish HIV-1 Replication

Krisko

Begum

Baker

et al. 2016

J Virol

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“…These models have successfully demonstrated the protective effects of microbicides (36,37). Additionally, researchers have observed viral escape from CD8 T cell immune pressure similar to that seen in HIV-infected humans and SIVinfected macaques (38). While these mice continue to be evaluated for the ability to recapitulate features of normal HIV pathogenesis, they will likely complement other approaches and models for the study of HIV.…”

Section: Discussionmentioning

confidence: 97%

Adoptive Transfer of Lymphocytes Isolated from Simian Immunodeficiency Virus SIVmac239Δnef-Vaccinated Macaques Does Not Affect Acute-Phase Viral Loads but May Reduce Chronic-Phase Viral Loads in Major Histocompatibility Complex-Matched Recipients

Greene

Lhost

Hines

et al. 2013

J Virol

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The live attenuated simian immunodeficiency virus (SIV) SIVmac239⌬nef is the most effective SIV/human immunodeficiency virus (HIV) vaccine in preclinical testing. An understanding of the mechanisms responsible for protection may provide important insights for the development of HIV vaccines. Leveraging the uniquely restricted genetic diversity of Mauritian cynomolgus macaques, we performed adoptive transfers between major histocompatibility complex (MHC)-matched animals to assess the role of cellular immunity in SIVmac239⌬nef protection. We vaccinated and mock vaccinated donor macaques and then harvested between 1.25 ؋ 10 9 and 3.0 ؋ 10 9 mononuclear cells from multiple tissues for transfer into 12 naive recipients, followed by challenge with pathogenic SIVmac239. Fluorescently labeled donor cells were detectable for at least 7 days posttransfer and trafficked to multiple tissues, including lung, lymph nodes, and other mucosal tissues. There was no difference between recipient macaques' peak or postpeak plasma viral loads. A very modest difference in viral loads during the chronic phase between vaccinated animal cell recipients and mock-vaccinated animal cell recipients did not reach significance (P ‫؍‬ 0.12). Interestingly, the SIVmac239 challenge virus accumulated escape mutations more rapidly in animals that received cells from vaccinated donors. These results may suggest that adoptive transfers influenced the course of infection despite the lack of significant differences in the viral loads among animals that received cells from vaccinated and mock-vaccinated donor animals.

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“…Such CD8 + T cell responses have been reported during Christian Münz 15 EBV, HIV, adeno-, influenza and dengue virus infection of HIS mice [26,40,62,63,66,72,78,[82][83][84]. The presence of HLA class I transgenes or HLA expressing human thymic tissue seems to favor the development of CD8 + T cell responses during viral infections, which recognize dominant T cell epitopes defined in human virus carriers [26,62,[82][83][84]. Mutational escape from these suggest that they are protective in vivo during HIV infection [83].…”

Section: Immune Surveillance In Mice With Reconstituted Human Immunementioning

confidence: 99%

“…The presence of HLA class I transgenes or HLA expressing human thymic tissue seems to favor the development of CD8 + T cell responses during viral infections, which recognize dominant T cell epitopes defined in human virus carriers [26,62,[82][83][84]. Mutational escape from these suggest that they are protective in vivo during HIV infection [83]. More directly, CD4 + and CD8 + T cells have been depleted with specific antibodies prior to some viral infections of HIS mice.…”

Section: Immune Surveillance In Mice With Reconstituted Human Immunementioning

confidence: 99%

Viral infections in mice with reconstituted human immune system components

Münz

2014

Immunology Letters

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Pathogenic viruses are often difficult to study due to their exclusive tropism for humans. The development of mice with human immune system components opens the possibility to study those human pathogens with a tropism for the human hematopoietic lineage in vivo. These include HCMV, EBV, KSHV, HIV, HTLV-1, dengue virus and JC virus. Furthermore, some human pathogens, like HSV-2, adenovirus, HCV, HBV and influenza A virus, with an additional tropism for somatic mouse tissues or for additional transplanted human tissues, mainly liver, have been explored in these models. The cellular tropism of these viruses, their associated diseases and primarily cell-mediated immune responses to these viral infections will be discussed in this review. Already some exciting information has been gained from these novel chimeric in vivo models and future avenues to gain more insights into the pathology, but also potential therapies, will be outlined. Although the respective in vivo models of human immune responses can still be significantly improved, they already provide preclinical systems for in vivo studies of important viral pathogens of humans. AbstractPathogenic viruses are often difficult to study due to their exclusive tropism for humans. The development of mice with human immune system components opens the possibility to study those human pathogens with a tropism for the human hematopoietic lineage in vivo. These include HCMV, EBV, KSHV, HIV, HTLV-1, dengue virus and JC virus. Furthermore, some human pathogens, like HSV-2, adenovirus, HCV, HBV and influenza A virus, with an additional tropism for somatic mouse tissues or for additional transplanted human tissues, mainly liver, have been explored in these models. The cellular tropism of these viruses, their associated diseases and primarily cell-mediated immune responses to these viral infections will be discussed in this review. Already some exciting information has been gained from these novel chimeric in vivo models and future avenues to gain more insights into the pathology, but also potential therapies, will be outlined. Although the respective in vivo models of human immune responses can still be significantly improved, they already provide preclinical systems for in vivo studies of important viral pathogens of humans.Christian Münz 3 Mice with reconstituted human immune system components as models of human immune responsesHuman immune responses can be studied in a correlative fashion in only a few tissues, which can be biopsied from patients or healthy individuals, including peripheral blood, some secondary lymphoid tissues, like tonsils, and the tumor microenvironment, assessing tumor infiltrating lymphocytes (TILs). For a more systematic analysis and in order to study the outcome of manipulations during immune responses, immunologists have primarily turned to the mouse as an in vivo animal model of mammalian immune responses. However, with a more and more detailed analysis of the mouse immune system it has become apparent that significant differences in ...

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Rapid Evolution of HIV-1 to Functional CD8 ⁺ T Cell Responses in Humanized BLT Mice

Cited by 101 publications

References 72 publications

APOBEC3G and APOBEC3F Act in Concert To Extinguish HIV-1 Replication

APOBEC3G and APOBEC3F Act in Concert To Extinguish HIV-1 Replication

Adoptive Transfer of Lymphocytes Isolated from Simian Immunodeficiency Virus SIVmac239Δnef-Vaccinated Macaques Does Not Affect Acute-Phase Viral Loads but May Reduce Chronic-Phase Viral Loads in Major Histocompatibility Complex-Matched Recipients

Viral infections in mice with reconstituted human immune system components

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Rapid Evolution of HIV-1 to Functional CD8 + T Cell Responses in Humanized BLT Mice

Cited by 101 publications

References 72 publications

APOBEC3G and APOBEC3F Act in Concert To Extinguish HIV-1 Replication

APOBEC3G and APOBEC3F Act in Concert To Extinguish HIV-1 Replication

Adoptive Transfer of Lymphocytes Isolated from Simian Immunodeficiency Virus SIVmac239Δnef-Vaccinated Macaques Does Not Affect Acute-Phase Viral Loads but May Reduce Chronic-Phase Viral Loads in Major Histocompatibility Complex-Matched Recipients

Viral infections in mice with reconstituted human immune system components

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Product

Resources

About

Rapid Evolution of HIV-1 to Functional CD8 ⁺ T Cell Responses in Humanized BLT Mice